Mutations of the genes BRCA1 and BRCA2 are thought to account for at least 70% of families with multiple cancers of the ovary and breast. Little is known about other predisposing genes in the remaining breast/ovarian cancer families, or in families with multiple ovarian cancers but little or no breast cancer. It is now feasible to identify other predisposing genes for ovarian cancer. Critical to this effort is DNA from many large ovarian cancer families. Because such families are rare, the Gilda Radner Familial Ovarian Cancer Registry is an important resource for such study. The Registry currently comprises records of more than 1,000 U.S. families reporting two or more ovarian cancer diagnoses. This application requests funds to identify 300 of the families, each containing two or more verified ovarian cancers in first- or second-degree relatives, for linkage analysis and study of gene environment interactions. Affected and unaffected members of each identified family will be asked to provide epidemiological and pedigree data and biological specimens for genetic analysis. We will classify the families as i) segregating mutations of BRCA1, ii) segregating mutations of other genes (BRCA2, MSH2, MLH1) or iii) containing no known mutations of these genes. To date, we have identified 156 participating families and genotyped 96 of them for BRCA1 and for part of BRCA2. Thirty of 96 genotyped families (31%) segregate BRCA1 mutations, and only one family has been found to segregate a BRCA2 mutation. Our goals are to: 1) pool families of type (iii) with similar families from the UK to map new genes associated with familial ovarian cancer; and 2) among women with BRCA1 mutations, evaluate associations relating ovarian cancer to epidemiological attributes such as parity, oral contraceptive use, and hormone replacement therapy. Use of this large registry to map predisposing genes for ovarian cancer and to characterize families segregating different types of mutations offers these benefits: it will identify women at genetically high risk who can be targeted for screening and intervention, it will allow classification of ovarian cancers into genetic subtypes, thereby facilitating the study of etiologic factors and the planning of strategies for screening and prevention, and it will provide a large database for examining lifestyle factors that modify ovarian cancer risk in carriers of mutations.